The aim of this study was to evaluate the crosstalk between Nrf2 and NF-κB signaling pathways and to explore the modulating activity actuated by
ferulic acid. In the
inflammation process, a key player is the nuclear factor-κB (NF-κB)
transcription factor pathway. On the contrary, the activation of Nrf2 inhibits
inflammation and impairs degenerative disease providing an interface between redox and anti-inflammatory responses. Recent studies have demonstrated that
protein phosphorylation of IKK complex is a potential mechanism for the activation of both Nrf2 and NF-κB pathways. The IKK complex is as an integration point for signals emanating from these different pathways. In this study, we demonstrated that
ferulic acid is able to regulate NF-κB and Nrf2 activities. Interestingly, we showed that
ferulic acid mimics the potent IKK inhibitor such as BMS, down-regulating the NF-κB response, TAK 1 activation and turning off Nrf2 activities in LPS-stimulated RAW 264.7 cells. Immunoblot data showed that the release of Nrf2 from Keap1 is maintained at low levels also in the presence of LPS stimulus. Nrf2 controls the expression of many
antioxidant and detoxification genes, by binding to antioxidant response elements (AREs) that are commonly found in the promoter region of
antioxidant (and other) genes. We demonstrated that in the pARE-Luc transfected cells the pre-treatment with FA significantly reduced LPS-induced (p<0.01) and BMS-induced (p<0.01) transcriptional activities. Analysis of well-known Nrf2 transcriptional targets showed that mRNAs expression of Nrf2-dependent
antioxidant and phase II
enzymes such as
dehydrogenase quinone1 (NQO1) and
glutathione S-transferase A2 (GSTA2) were up-regulated by BMS and significantly increase more by association with LPS, but are down-regulated in the presence of FA. Interestingly, cells depleted of Keap1 showed increased response of the Nrf2 transcriptional activity also in the presence of FA, strongly suggesting its modulating role in Keap1-Nrf2 signaling pathway.